Elmira Ramezani, Zahra Sadeghloo, Mehdi Azizmohammad Looha, Amir Sadeghi
Helicobacter pylori is globally recognized for its role in chronic gastritis, peptic ulcer disease, and gastric cancer. Yet despite decades of research and standardized eradication protocols, treatment failures and disease recurrence remain frustratingly common. While antibiotic resistance has been a central focus, emerging data suggest that H. pylori employ additional, underappreciated survival strategies that extend its pathogenic potential beyond the stomach. This review redefines H. pylori as a versatile pathogen capable of persisting through underappreciated survival strategies: the coccoid viable but non-culturable (VBNC) state, intracellular survival within yeast cells, and the release of outer membrane vesicles (OMVs). Each of these forms confers unique advantages: coccoid cells withstand environmental stress and evade standard diagnostics; yeast-harbored H. pylori may resist antibiotics, enable vertical transmission, and serve as long-term reservoirs; and OMVs can traffic toxins like VacA and CagA to distant tissues, triggering inflammation, apoptosis, and barrier dysfunction without bacterial contact. This review proposes that these alternative forms are not incidental anomalies, but integral to H. pylori’s persistence, dissemination, and disease spectrum, including potential extra-gastric effects. Recognizing and targeting these hidden states may hold the key to improved diagnostics, more durable eradication, and a deeper understanding of one of medicine’s most enduring pathogens.